Paclitaxel AUC Research Articles

OGC O03 Patient-derived oesophageal adenocarcinoma organoids may predict response to induction therapies in oesophageal cancer

Abstract Background The current management of locally-advanced oesophageal adenocarcinoma (OAC) includes neoadjuvant therapy; however, there are no robust markers that predict treatment response. While 25% of patients will have a complete pathological response, up to 40% will have little or no response. Identification of this non-responsive subgroup prior to treatment and robust testing with alternative drug panels may help to generate personalised induction regimens. Patient derived organoids have shown some promise in other cancers as a model for personalised therapy. The aim of this study is to determine the feasibility of utilising PDOs to predict response to induction therapy. Methods PDOs were generated from endoscopic biopsies taken pre-treatment in patients with locally advanced (LA) or metastatic (M) esophageal cancer. For those with LA disease, samples were also taken post-resection. PDOs were established, passaged, then treated with a drug panel of platinum-based drugs, taxane-based drugs, topoisomerase inhibitors and 5-flurouracil. Treatment response curves and growth metrics were mapped back to treatment response, based on pathological tumour regression grade in the LA group and clinical response based on cross-sectional imaging in the M group. Results 19 organoids from 7 LA tumours[YJ1] [JB2] and 10 organoids from 8 M tumours were treated. For LA PDOs, there were significant correlations between cisplatin IC50 (p=0.007), EC50 (p=0.002) and TRG. There was a correlation between paclitaxel AUC and TRG (p=0.02). For PDOs treated with irinotecan, there was an in-vitro response in 45% of organoids which had no clinical response to induction therapy. None of these patients received a topoisomerase inhibitor in their induction therapy. For PDOs treated with 5-FU, 41% of those with no response to induction therapy showed an in vitro response to treatment. Those organoids showing a response had not received 5-FU as part of induction. For M PDOs, there was a correlation between cisplatin and clinical response for AUC (p=0.04), and a trend for IC50 (p=0.07). There were also correlations between paclitaxel and clinical response for IC50 (p=0.04) and AUC (p=0.01). There were no correlations with irinotecan or 5-FU in this subset. These results raise the possibility that the response of PDOs to drug treatments in vitro may in future be used to develop personalised drug induction regimens for patients with esophageal cancer. Conclusions Treatment responses of OAC PDOs treated in vitro with standard chemotherapeutic agents may predict clinical response in the corresponding patient's tumor. A PDO model may form the basis for screening therapeutic agents in the neoadjuvant window, allowing the development of truly personalised neoadjuvant strategies. Further in vitro and in vivo testing is warranted to determine how these models may be applied to a clinical context.

315. PATIENT-DERIVED ESOPHAGEAL ADENOCARCINOMA ORGANOIDS TREATED WITH CHEMOTHERAPEUTIC AGENTS MAY PREDICT TUMOR RESPONSE IN VIVO

Abstract The current management of locally-advanced esophageal adenocarcinoma (EAC) includes neoadjuvant therapy; however, there are no robust markers that predict treatment response. While 25% of patients will have a complete pathological response, up to 40% will have little or no response. Identification of this non-responsive subgroup prior to treatment could allow personalization of induction regimens. This study aims to determine the feasibility of using patient-derived organoids (PDOs) generated from EAC to predict induction treatment response. PDOs were generated from endoscopic biopsies taken pre-treatment in patients with locally advanced (LA) or metastatic (M) esophageal cancer. For those with LA disease, samples were also taken post-resection. PDOs were established, passaged, then treated with a drug panel of platinum-based drugs, taxane-based drugs, topoisomerase inhibitors and 5-flurouracil. Treatment response curves and growth metrics were mapped back to treatment response, based on pathological tumor regression grade in the LA group and clinical response based on cross-sectional imaging in the M group. 19 organoids from 7 LA tumors and 10 organoids from 8 M tumors were treated. For LA PDOs, there were significant correlations between cisplatin IC50 (p = 0.007), EC50 (p = 0.002) and TRG. There was a correlation between paclitaxel AUC and TRG (p = 0.02). There were no correlations with irinotecan or 5-FU drug metrics and TRG. For M PDOs, there was a correlation between cisplatin and clinical response for AUC (p = 0.04), and a trend for IC50 (p = 0.07). There were also correlations between paclitaxel and clinical response for IC50 (p = 0.04) and AUC (p = 0.01). There were no correlations with irinotecan or 5-FU. Treatment responses of EAC PDOs treated in vitro with standard chemotherapeutic agents may predict clinical response in the corresponding patient’s tumor. A PDO model may form the basis for screening therapeutic agents in the neoadjuvant window, allowing the development of truly personalized neoadjuvant strategies.

Abstract D052: Pharmacokinetic analysis of co-formulation of calcipotriol and paclitaxel for pancreatic ductal adenocarcinoma shows reduced systemic exposures and eliminations: Implications for safety and efficacy

Abstract Introduction: The 5-year survival rate for Pancreatic Ductal Adenocarcinoma (PDAC) remains 7%. An emerging treatment strategy involves the combination of vitamin D receptor (VDR) ligands with chemotherapeutic agents to re-program the activated cancer-associated fibroblast (CAFs). Calcipotriol (CAP), a synthetic analogue of vitamin D can reprogram CAFs, but is toxic with side effects including cachexia and edema. Due to the abundance of the VDR in the body, diminished plasma exposure and elimination of calcipotriol together with enhanced accumulation in the tumor are desirable to reduce toxicity and increase efficacy. We propose to achieve this with a slow-releasing micellar nanoformulation with a well-controlled size to take advantage of the leaky tumor fenestrations and enhance delivery. Method: 8-week old male C57BL/6 mice were administered with either formulated or non-formulated single IV bolus dose of CAP and paclitaxel (PTX). Drugs from blood samples were extracted, and simultaneously quantified using validated LC-MS/MS assay. Pharmacokinetic modeling was performed with Phoenix® WinNonlin (8.0) using 2-compartment model. Results: Our co-formulation of CAP and PTX resulted in >2-fold decrease in plasma exposure (AUC) and 5-fold reduction of peak concentration (Cmax) of CAP. Similarly, PTX AUC and Cmax were halved in mice administered with the formulated drugs. The PTX total clearance (CL) was similar between both groups, but CAP CL was 5-fold lower in formulation-administered mice. Further, CAP elimination (k10) from central compartment and from central to peripheral compartments (k12) were 2 and >3-fold slower, respectively, in the formulation group. The reverse elimination (k21) are similar. Similarly, the k10 of PTX was almost halved, while the k12 was 44-fold slower in mice receiving formulated drugs. The reverse elimination from the peripheral to the central compartment (k21) for formulated PTX is almost 10 times slower than in the mice receiving non-formulated PTX. Conclusion: Our micellar co-formulation of CAP and PTX is able to reduce total clearance of these agents from the systemic circulation. Further, rate constants derived show that PTX elimination from the systemic circulation to tissues is very slow and we expect this to correlate with an extended duration of action of this drug. Finally, our formulation halved the systemic exposure and peak concentrations of CAP that should lead to a more favorable safety profile of this agent. Ongoing work will focus on studying the pharmacokinetics of co-formulated CAP and PTX in a larger cohort of animals and we eventually hope to demonstrate the therapeutic merits of our nanoformulation strategy in pancreatic tumor-bearing mice. Citation Format: Victor R Lincha, Jun Zhao, Chun Li, Diana S-L Chow. Pharmacokinetic analysis of co-formulation of calcipotriol and paclitaxel for pancreatic ductal adenocarcinoma shows reduced systemic exposures and eliminations: Implications for safety and efficacy [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D052.

Electro-Acupuncture Promotes Accumulation of Paclitaxel by Altering Tumor Microvasculature and Microenvironment in Breast Cancer of Mice.

Targeted drug delivery could increase the efficacy of chemotherapy, however, a plethora of obstacles exist in the current targeted delivery designs. In this study, we introduce a novel avenue of targeted drug delivery using electro-acupuncture and evaluate its effect on the distribution of paclitaxel in a breast cancer mouse model. Our results show that electro-acupuncture intervention significantly increased the intratumoral concentration of paclitaxel. The mice in acupuncture group showed shorter tmax, longer t1/2 and higher AUC of paclitaxel as compared with that in paclitaxel-only group. Moreover, we found that the acupuncture intervention significantly induced cell apoptosis in tumors. The levels of COL IV and α-SMA increased in tumors of acupuncture group. The negative tumor metastasis biomarker, NM23, was significantly upregulated in tumors of mice in acupuncture group. Our results suggest that acupuncture intervention around the tumor area increases the local concentration of chemotherapeutic agents. The targeted effect of acupuncture is achieved by altering tumor microvasculature and microenvironment. Therefore, combined therapy of acupuncture with chemotherapeutic agents is promising in improving cancer treatment efficacy.

PEG-derivatized octacosanol as micellar carrier for paclitaxel delivery

In this study, PEG-derivatized octacosanol copolymer was successfully developed to improve the anti-tumor activity and eliminate toxicity of the commercial formulation of paclitaxel (PTX). MPEG2K-C28, the conjugation of monomethoxy Poly(ethylene glycol) 2000 and octacosanol, was readily soluble in aqueous solution and self-assembled to form micelles with small sizes (<20nm) that are efficient in encapsulating PTX with a drug loading of 9.38±0.18% and an encapsulation efficiency of 93.90±2.12%. Meanwhile, octacosanol is very safe for humans and amazingly exhibits antitumor activity through inhibition activity of matrix metalloproteinases (MMPs) and translocation of the transcription factor (nuclear factor-kappa B, NF-κB) to the nucleus, which may be able to promote synergistic effects with PTX. A sustained and slower in vitro release behavior was observed in the (PTX micelles) than that of Taxol. PTX micelles exhibited more potent cytotoxicity than Taxol in the 4T1 breast cancer cell line. More interestingly, MPEG2K-C28 selectively inhibited the growth of 4T1 cells rather than the normal cells (HEK293 and L929 cell lines), indicating the antitumor activity of octacosanol remained after conjugation with MPEG. Acute toxicity evaluations indicated that MPEG2K-C28 was a safe drug carrier. Pharmacokinetic study revealed that PTX micelles improved the T1/2 and AUC of PTX (compared with Taxol) from 1.910±0.139h and 13.999±1.109mg/l×h to 2.876±0.532h and 76.462±8.619mg/l×h in vivo, respectively. The maximal tolerated dose (MTD) for PTX micelles (ca. 120mg PTX/kg) in mice was significantly higher than that for Taxol (ca. 20mg PTX/kg). PTX micelles exhibited slightly better antitumor activity than Taxol but safer in 4T1 breast cancer model in vivo. The cell apoptosis in the immunofluorescent studies and the cell proliferation in the immunohistochemical studies also proved the results. In conclusion, MPEG2K-C28 is a simple, safe and effective drug delivery carrier for PTX, and has some therapeutic effects in 4T1 cells in vitro. PTX micelles showed significant antitumor activity in vivo with low systemic toxicity in 4T1 breast cancer. MPEG2K-C28 micelles entrapping PTX deserve more studies in the future.

In vivo pharmacokinetics, biodistribution and antitumor effect of paclitaxel-loaded micelles based on α-tocopherol succinate-modified chitosan

In our previous study, α-tocopherol succinate modified chitosan (CS-TOS) was synthesized and encapsulated paclitaxel (PTX) to form micelles. Preliminary study revealed that the CS-TOS was a potential micellar carrier for PTX. In this study, some further researches were done using Taxol formulation as the control to evaluate the micelle system deeply. In vitro cell experiments demonstrated that the cytotoxic effect of PTX-loaded CS-TOS micelles against MCF-7 cells was comparable with that of Taxol formulation, and the PTX-loaded micelles had excellent cellular uptake ability, which was in a time-dependent manner. The in vivo pharmacokinetic study in rats showed that the micelles prolonged the half-life and increased AUC of PTX than Taxol formulation. From biodistribution study, it was clear that for micelles, the drug concentrations in the liver and spleen were significantly higher than those of Taxol formulation, but much lower in the heart and kidney. Furthermore, the PTX-loaded micelles showed superior antitumor effect, but yielded less toxicity as indicated by the results of antitumor efficacy study and survival study in U14 tumor-bearing mice. These results suggested that CS-TOS micelles could be a potentially useful drug delivery system to improve the performance and safety of PTX.

Pharmacokinetic drug-drug interaction assessment of peptibody trebananib in combination with chemotherapies.

To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types. PK data of trebananib and chemotherapies (paclitaxel, carboplatin, pegylated liposomal doxorubicin, topotecan, capecitabine, lapatinib, 5-FU, irinotecan, or docetaxel) were collected from trials of ovarian cancer, metastatic breast cancer, colorectal carcinoma, and mixed solid tumor. A dedicated PK DDI study of trebananib and paclitaxel in patients with mixed solid tumors was also conducted. The geometric least squares mean (GLSM) ratios and corresponding 90% confidence intervals (CI) of C max and AUC were estimated for DDI evaluations. In the PK DDI study of trebananib and paclitaxel, the GLSM ratio (90% CI) was 1.17 (1.10-1.25) for paclitaxel AUC and 1.30 (1.15-1.48) for paclitaxel C max. The GLSM ratio (90% CI) for the effect of paclitaxel on trebananib PK was 0.92 (0.87-0.97) for trebananib AUC and 0.98 (0.92-1.05) for trebananib C max. In the remaining studies, the GLSM ratios (90% CI) of C max and AUC generally ranged from 0.8 to 1.25 or exhibited less than twofold PK variabilities across chemotherapeutic agents. No dose-dependent DDIs were evident. No PK DDI was deemed clinically meaningful between trebananib and the tested chemotherapeutic agents to warrant dose adjustments.

Enhanced oral bioavailability and anti‐tumour effect of paclitaxel by 20(s)‐ginsenoside Rg3in vivo

The purpose of this study was to investigate the effect of paclitaxel in combination with 20(s)-ginsenoside Rg3 on its anti-tumour effect in nude mice. In the Caco-2 transport assay, the apparent permeability from the apical side to the basal side (P(app)) (A-B) and P(app) (B-A) of paclitaxel were measured when co-incubated with different concentrations of 20(s)-ginsenoside Rg3. The results indicated that the penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Meanwhile, 20(s)-ginsenoside Rg3 inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The pharmacokinetic parameters of paclitaxel after oral co-administration of paclitaxel (40 mg/kg) with various doses of 20(s)-ginsenoside Rg3 in rats were investigated by an in vivo pharmacokinetic experiment. The results showed that the AUC of paclitaxel co-administered with 20(s)-ginsenoside Rg3 was significantly higher (p < 0.001 at 10 mg/kg) compared with the control. The relative bioavailability (RB) % of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. The effect of paclitaxel orally co-administered with 20(s)-ginsenoside Rg3 against human tumour MCF-7 xenografts in nude mice was also evaluated. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumour activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05). The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumour activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route.

Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin

Concurrent delivery of multiple poorly water-soluble anticancer drugs has been a great challenge due to the toxicities exerted by different surfactants or organic solvents used in solubilizing individual drugs. We previously found that poly(ethylene glycol)-block-poly(D, l-lactic acid) (PEG-b-PLA) micelles can serve as a safe delivery platform for simultaneous delivery of paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP) to mice. The high tolerance of this polymeric micelle formulation by mice allowed us to investigate the pharmacokinetics of the 3 co-delivered drugs. In this study, it was shown that 3-in-1 PEG-b-PLA micelle delivering high doses of PTX, 17-AAG, and RAP (60, 60, and 30mg/kg, respectively) significantly increased the values of the area under the plasma concentration–time curves (AUC) of PTX and RAP in mice compared to the drugs delivered individually, while the pharmacokinetic parameters of 17-AAG were similar in both 3-in-1 and single drug-loaded PEG-b-PLA micelle formulations. Moreover, pharmacokinetic study using 2-in-1 micelles indicated that the augmented AUC value of RAP was due to the co-delivery of 17-AAG, while the increase in AUC of PTX was more likely caused by the co-delivery of RAP. In contrast, when 3-in-1 and single drug-loaded PEG-b-PLA micelles were administrated at modest dose (PTX, 17-AAG, and RAP at 10, 10, and 5mg/kg, respectively), pharmacokinetic differences of individual drugs between 3-in-1 and single drug formulations were eliminated. These results suggest that 3-in-1 PEG-b-PLA micelles can concurrently deliver PTX, 17-AAG, and RAP without changing the pharmacokinetics of each drug at modest doses, but altered pharmacokinetic profiles emerge when drugs are delivered at higher doses.

Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion

Paclitaxel is a potent anti-cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor-free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti-tumour efficacy of the PSD compared with Taxol. SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti-tumor activity of PSD was assessed in an in vivo anti-tumor nude mice model inoculated with human SKOV-3 cancer cells. The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84-fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti-tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose. These results suggest that the PSD, a CrEL-free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.

Pharmacokinetic study of the phase III, randomized, double-blind, multicenter trial (TRIBUTE) of paclitaxel and carboplatin combined with erlotinib or placebo in patients with advanced Non-small Cell Lung Cancer (NSCLC)

To assess the pharmacokinetics and evaluate potential drug-drug interactions between erlotinib, paclitaxel and carboplatin. 1,079 previously untreated patients with advanced NSCLC were enrolled and randomized in a phase III trial (TRIBUTE) to receive either erlotinib or placebo in combination with paclitaxel 200 mg/m2 IV over 3 h and carboplatin at a calculated dose to achieve an AUC 6 mg∙min/mL. To determine possible drug-drug interaction with this combination, a subset of 24 (12 erlotinib, 12 placebo) patients were enrolled onto an intensive pharmacokinetic (IPK) substudy group at a single site. All IPK patients received either erlotinib 150 mg/day or placebo-controlled tablets. Analyses were completed using validated analytical methodologies. Non-compartmental modeling was utilized to estimate PK parameters. Complete blood sampling for pharmacokinetic analysis was obtained in 21 of 24 patients. Mean AUC(0-τ) for erlotinib and the OSI-420 metabolite were 29,997 ng∙h/mL and 3,020 ng∙h/mL, respectively. Mean (SD) paclitaxel clearances (L/h/M(2)) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel AUC(0-∞) (ng∙h/mL) was 18,400 (5,300) for the placebo group and 17,800 (5,500) for the erlotinib group. For carboplatin, the mean (SD) clearances (L/h) were 16.8 (3.9) and 16.1 (4.4) for the placebo and erlotinib groups, respectively. The resultant carboplatin AUC(0-∞) (ng/mL∙h) were 49,900 (9,700) for the placebo group and 48,400 (11,900) for the erlotinib group. No significant differences were observed in these paclitaxel or carboplatin pharmacokinetic group comparisons. The addition of erlotinib to a standard chemotherapy regimen for NSCLC did not alter the systemic exposures (AUC(0-∞)) of paclitaxel (p = 0.80) and carboplatin (p = 0.756) when erlotinib-treated patients were compared to placebo-treated patients. The pharmacokinetics of erlotinib and its metabolite OSI-420 did not appear to be altered by the concomitant administration of paclitaxel and carboplatin.

Nab‐Paclitaxel: a bright new SPARC in taxane therapy of cancer

Nab‐Paclitaxel: a bright new SPARC in taxane therapy of cancer

Oral microemulsions of paclitaxel: In situ and pharmacokinetic studies

The overall goal of this study was to develop cremophor-free oral microemulsions of paclitaxel (PAC) to enhance its permeability and oral absorption. The mechanism of this enhancement, as well as characteristics of the microemulsions relevant to the increase in permeability and absorption of the low solubility, low permeability PAC was investigated. Phase diagrams were used to determine the macroscopic phase behavior of the microemulsions and to compare the efficiency of different surfactant-oil mixtures to incorporate water. The microemulsion region on the phase diagrams utilizing surfactant-myvacet oil combinations was in decreasing order: lecithin: butanol: myvacet oil (LBM, 48.5%) > centromix CPS: 1-butanol: myvacet oil (CPS, 45.15%) > capmul MCM: polysorbate 80: myvacet oil (CPM, 27.6%) > capryol 90: polysorbate 80: myvacet oil (CP-P80, 23.9%) > capmul: myvacet oil (CM, 20%). Oil-in-water (o/w) microemulsions had larger droplet sizes (687–1010 nm) than the water-in-oil (w/o) microemulsions (272–363 nm) when measured using a Zetasizer nano series particle size analyzer. Utilizing nuclear magnetic resonance spectroscopy (NMR), the self-diffusion coefficient ( D) of PAC in CM, LBM and CPM containing 10% of deuterium oxide (D 2O) was 2.24 × 10 −11, 1.97 × 10 −11 and 0.51 × 10 −11 m 2/s, respectively. These values indicate the faster molecular mobility of PAC in the two w/o microemulsions (CM and LBM) than the o/w microemulsion – CPM. The in situ permeability of PAC through male CD-IGS rat intestine was 3- and 11-fold higher from LBM and CM, respectively, than that from the control clinical formulation, Taxol ® (CE, cremophor: ethanol) in a single pass perfusion study. PAC permeability was significantly increased in the presence of the pgp/CYP3A4 inhibitor cyclosporine A (CsA). This enhancement may be attributed to the pgp inhibitory effect of the surfactants, oil and/or the membrane perturbation effect of the surfactants. The oral disposition of PAC in CM, LBM and CPM compared to CE was studied in male CD-IGS rats after a single oral dose (20 mg/kg). The area-under-the-curve of PAC in CM was significantly larger than LBM, CPM and CE. Oral microemulsions of PAC were developed that increased both the permeability and AUC of PAC as compared to CE.

Phase I study of the safety, tolerability, and pharmacokinetics (PK) of weekly paclitaxel administered in combination with pazopanib (GW786034)

3552 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit with demonstrated activity in renal cell cancer, sarcoma, and ovarian cancer when administered at 800 mg daily. Improved efficacy of weekly paclitaxel with the anti-VEGF agent bevacizumab in metastatic breast cancer provides a rationale for combining an angiogenesis inhibitor with a taxane. Methods: Patients (pts) with advanced cancer (ECOG PS 0–1) were eligible. Dose escalations of paclitaxel (15–80 mg/m2) on days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) daily were evaluated for safety, PK, and clinical response. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK; the optimally tolerated regimen (OTR) consisted of ≤ 1/6 pts experiencing a DLT; 9 additional pts were enrolled to confirm the OTR. Results: 25 pts received paclitaxel/pazopanib at doses of 15/400 (3), 15/800 (3), 50/800 (3) and 80/800 (16) mg. Median age was 58 y; M: 48%; 92% Caucasian. Most common tumor types were breast (5), CRC (3), esophageal (3), and NSCLC (3). Most frequent adverse events (AEs) (mostly Gr 1/2) were nausea (68%), fatigue (56%), diarrhea (52%), vomiting (48%), rash (44%), anorexia (32%), visual disturbance (24%), alopecia (24%), and constipation (24%). Hepatic enzyme elevations: ALT (48%), AST (44%), alkaline phosphatase (24%), and bilirubin (12%) were mainly Gr 1/2. The OTR was defined as 80 mg/m2 paclitaxel and 800 mg pazopanib (median 2.5 cycles [range 1–8]; median no. of 2 prior regimens [range 1–5]); 1 DLT (Gr 3 groin abscess) was observed at this dose. 12/16 pts at the OTR required dose modifications; 3 of these were withdrawn due to an AE. For pazopanib, 7 pts required interruptions and 3 pts required dose reductions. For paclitaxel, 11 pts required interruptions/delays and 5 pts required dose reductions. Liver enzyme elevation was the most common reason for dose modification. Pazopanib increased mean paclitaxel AUC (45%) and Cmax (40%). Clinical activity at the OTR: PR in 5/16 (31%) pts and SD > 8 wks in 10/16 (63%) pts. Conclusions: Therapeutic doses of daily pazopanib and weekly paclitaxel can be combined with a manageable toxicity profile and evidence of clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline Eli Lilly, Genentech™ BioOncology Aventis, Celgene, GlaxoSmithKline, OSI Oncology

Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin®, in resistant solid tumor malignancies

To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel (DHA-paclitaxel), a taxane fatty acid conjugate. Docosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel 200 mg/m(2) was dose escalated by 100 mg/m(2) per cohort to 600 mg/m(2). Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were collected. Twenty-one patients received 42 cycles of treatment over five dose levels. Grade 3/4 neutropenia occurred in five patients but was not dose limiting. Grade 3 hyperbilirubinemia, a DLT, and grade 1 sensory neuropathy occurred at the highest dose level. PK analyses demonstrated dose proportional C (max) and AUC(0-24). Limited accumulation of DHA-paclitaxel or paclitaxel occurred with weekly treatment. Increased DHA-paclitaxel and paclitaxel AUC(0-24) were associated with increased neutropenia. Of the 19 patients evaluable for response, three patients with esophageal, melanoma and colon carcinoma had stable disease for 11, 16, and 17 weeks, respectively. Docosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600 mg/m(2) was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3 week or weekly taxanes.

Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic–pharmacodynamic study

To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m(-2), depending on liver impairment. Covariate and semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer (n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity (R2 = -0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling (P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK-PD model (P < 10(-4)). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III-V. Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials.

A pharmacokinetic study of Genetaxyl (G) together with cyclosporin A (CsA) administered orally in cancer patients

12002 Background: Oral administration of paclitaxel given with CsA has shown promising activity in Phase II trials, but the apparent bioavailability is low and dose-dependent due to the presence of high concentrations of Cremophor EL (CrEL). We hypothesized that the use of a novel oral paclitaxel formulation containing only 20% CrEL (Genetaxyl [G]; Genovate Biotechnology Ltd., Taiwan), given with CsA is associated with an improved pharmacokinetic (PK) profile. Methods: Cohorts of 6 patients with cancer were treated with oral G at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received IV G (175 mg/m2, 3-h infusion). Three additional patients received generic IV paclitaxel (GIP). Serial blood samples were analyzed by LC/MS/MS and equilibrium dialysis, to determine total and unbound paclitaxel PK. Results: The mean (± SD) total paclitaxel AUCs were 1299±189, 1682±636, and 2204±1407 ng.h/mL at the 3 consecutive dose levels, suggesting nonlinear PK. However, based on unbound AUC, the oral bioavailability was dose-independent (P=.62), with a mean value of 37.2±18.6% (n=15). As expected, the total paclitaxel AUC following IV G (9024±4648 ng·h/mL) was lower than that for IV GIP (13,732±3983 ng·h/mL), as a result of increased clearance (39.6 vs 18.3 L/h) and a larger volume of distribution (768 vs 268 L). Interestingly, the unbound paclitaxel AUC was similar between the two IV formulations (P=.25), as the ratio of unbound/total paclitaxel for G was 2.5 times higher than that for GIP (12.5 vs 4.9%). Toxicity profiles were mild, with only 2 patients experiencing ≥ Gr 3 myelosuppression following oral G at 180 mg/m2. Conclusions: The mean bioavailability of paclitaxel following oral Genetaxyl with CsA was about 37%, which is higher than that observed previously with paclitaxel (range, 21–31%). Further clinical exploration of oral Genetaxyl in taxane-sensitive diseases is warranted. [Table: see text]

Paclitaxel and pegylated liposomal doxorubicin in recurrent head/neck cancer: An unexpected administration interval-dependent pharmacokinetic interaction

2042 Background: Combination of paclitaxel (PTX) with pegylated liposomal doxorubicin (PLD) is an interesting opportunity for recurrent head/neck cancer treatment. Their pharmacokinetic (PK) behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but also on different iv administration interval between the two drugs. The study endpoint was to evaluate any possible administration interval-dependent PK interaction, when PLD infusion start is delayed from 0 to 24 h after PTX infusion end. Methods: 24 patients affected by recurrent cisplatin pre-treated squamous cellhead/neck cancer were enrolled, receiving PTX 80 mg/m2 q 1w and PLD 12.5 mg/m2 q 2w for 6w/2w rest. Administration interval was 0 h at d1 (PTX-PLD 0) and 24 h at d15 (PTX-PLD 24). Blood sampling was performed at d1–15, PTX and PLD blood levels were analyzed by high performance liquid chromatography techniques, while PK parameters by non-compartmental analysis. Results: PTX PK parameters had large statistically significant differences (median/IQR, PTX-PLD 0 vs. PTX-PLD 24, Mann-Whitney test): Cmax 261/219–531 vs. 407/250–1473 ng/ml p=0.142, AUC 869/688–1331 vs. 3361/969–7853 ng*h/ml p=0.013, Kel 0.39/0.26–0.57 vs. 0.11/0.02–0.26 h⁁−1 p=0.001, Cl 153/89–198 vs. 41/17–138 l/h p=0.013. Similarly, PLD Cmax and AUC were higher in PTX-PLD 24 (Cmax 5.1/3.3–8.1 vs. 6.8/5.3–7.8 mg/l p=0.043, AUC 341/104–1472 vs. 603/106–1006 mg*h/l p=1.000). The overall response rate was 37.5%, including 1 CR (4%); median response duration was 5.5 months (range, 2–16), median overall survival 10 months (range, 2–25+). Conclusions: This exploratory study, having a favourable palliative role in heavily pre-treated patients, showed that PTX PK profile is unexpectedly affected by a different administration interval. In PTX-PLD 0, PTX AUC is fourfold reduced, with a similar increase in Cl, totally due to Kel alteration: therefore, patients could be underexposed to PTX. PLD PK behavior confirmed previous studies results, in which PTX modified PLD disposition, prolonging the duration of its elimination phase and increasing total body exposure to PLD. No significant financial relationships to disclose.

Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats

The purpose of this study was to investigate the effect of morin on the pharmacokinetics of orally and intravenously administered paclitaxel in rats. Pharmacokinetic parameters of paclitaxel were determined in rats after an oral (30 mg kg −1) or intravenous (3 mg kg −1) administration of paclitaxel to rats in the presence and absence of morin (3.3 and 10 mg kg −1). Compared to the control given paclitaxel alone, pretreatment with morin 30 min prior to the oral administration of paclitaxel increased C max and AUC of paclitaxel by 70–90% and 30–70%, respectively, while there was no significant change in T max and terminal plasma half-life ( T 1/2) of paclitaxel. Consequently, absolute and relative bioavailability values of paclitaxel in the rats after the pretreatment with morin were significantly higher ( p < 0.05) than those from the control. In contrast, following an intravenous administration of paclitaxel (3.3 mg kg −1), the pharmacokinetic profiles of paclitaxel were not altered significantly in the presence of morin. Those results suggest that the enhanced oral exposure of paclitaxel should be mainly due to the inhibition effect of morin on the gastrointestinal extraction of paclitaxel during the intestinal absorption. Therefore, the concurrent use of morin or morin-containing dietary supplement may provide a therapeutic benefit in the oral delivery of paclitaxel.

Prospective Evaluation of the Relationship of Patient Age and Paclitaxel Clinical Pharmacology: Cancer and Leukemia Group B (CALGB 9762)

To prospectively evaluate the pharmacokinetics and toxicity profile of paclitaxel in relation to patient age in adults > or = 55 years old. Paclitaxel was administered at 175 mg/m2 for 3 hours to 153 patients, 46 of whom were > or = 75 years of age. Pharmacokinetic and toxicity assessments were performed. Data were analyzed by cohort (cohort 1, age 55 to 64 years; cohort 2, age 65 to 74 years; cohort 3, age > or = 75 years). Paclitaxel concentration versus time (AUC) and total-body clearance (CL(tb)) data were available for 122 patients (cohort 1, 46 patients; cohort 2, 44 patients; cohort 3, 32 patients). Mean paclitaxel AUC increased across cohorts (P = .01). Mean (SE) AUCs were 22.4 (2.5) micromol/L x hour, 26.2 (2.8) micromol/L x hour, and 31.7 (5.6) micromol/L x hour for cohorts 1, 2, and 3, respectively. There was a corresponding significant (P = .007) age-related decrease in mean (SE) paclitaxel CL(tb) (cohort 1, 11.0 [0.7] L/h/m2; cohort 2, 9.3 [0.6] L/h/m2; cohort 3, 8.2 [0.6] L/h/m2). Patients in cohort 3 experienced significantly lower absolute neutrophil count nadirs than did younger groups (P = .02). There was also a significant increase in percentage of patients with > or = grade 3 neutropenia across age cohorts (cohort 1, 22%; cohort 2, 35%; cohort 3, 49%; P = .006). However, the increased exposure of patients to paclitaxel and increased neutropenia were not reflected in adverse clinical sequelae such as hospitalization for toxicity (P = .82), receiving intravenous antibiotics (P = .21), or experiencing a temperature more than 38 degrees C (P = .45). Although paclitaxel CL(tb) decreases with increasing patient age, there is great interpatient variability. Cooperative group studies to evaluate the effect of aging on pharmacokinetics are feasible.